Nef proteins from diverse groups of primate lentiviruses downmodulate CXCR4 to inhibit migration to the chemokine stromal derived factor 1

Hrecka, K., Swigut, T., Schindler, M., Kirchhoff, F., Skowronski, J. (August 2005) Nef proteins from diverse groups of primate lentiviruses downmodulate CXCR4 to inhibit migration to the chemokine stromal derived factor 1. J Virol, 79 (16). pp. 10650-9. ISSN 0022-538X (Print)

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DOI: 10.1128/jvi.79.16.10650-10659.2005


Nef proteins of primate lentiviruses promote viral replication, virion infectivity, and evasion of antiviral immune responses by modulating signal transduction pathways and downregulating expression of receptors at the cell surface that are important for efficient antigen-specific responses, such as CD4, CD28, T-cell antigen receptor, and class I and class II major histocompatibility complex. Here we show that Nef proteins from diverse groups of primate lentiviruses which do not require the chemokine receptor CXCR4 for entry into target cells strongly downmodulate the cell surface expression of CXCR4. In contrast, all human immunodeficiency virus type 1 (HIV-1) and the majority of HIV-2 Nef proteins tested did not have such strong effects. SIVmac239 Nef strongly inhibited lymphocyte migration to CXCR4 ligand, the chemokine stromal derived factor 1 (SDF-1). SIVmac239 Nef downregulated CXCR4 by accelerating the rate of its endocytosis. Downmodulation of CXCR4 was abolished by mutations that disrupt the constitutively strong AP-2 clathrin adaptor binding element located in the N-terminal region of the Nef molecule, suggesting that Nef accelerates CXCR4 endocytosis via an AP-2-dependent pathway. Together, these results point to CXCR4 as playing an important role in simian immunodeficiency virus and possibly also HIV-2 persistence in vivo that is unrelated to viral entry into target cells. We speculate that Nef targets CXCR4 to disrupt ordered trafficking of infected leukocytes between local microenvironments in order to facilitate their dissemination and/or impair the antiviral immune response.

Item Type: Paper
Uncontrolled Keywords: Antigens CD4 physiology Cell Movement Chemokines CXC physiology Nef Down-Regulation Endocytosis Gene Products nef/chemistry physiology HIV physiology Humans Jurkat Cells Receptors CXCR4 antagonists & inhibitors physiology Simian immunodeficiency virus physiology T-Lymphocytes physiology
Subjects: organism description > virus > lentivirus
CSHL Authors:
Communities: CSHL labs > Skowronski lab
Depositing User: CSHL Librarian
Date: August 2005
Date Deposited: 12 Jan 2012 20:10
Last Modified: 07 May 2018 15:27
PMCID: PMC1182621
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